Noninvasive Early Identification of Therapeutic Benefit from Immune Checkpoint Inhibition.

Although treatment of non-small cell lung cancer (NSCLC) with immune checkpoint inhibitors (ICIs) can produce remarkably durable responses, most patients develop early disease progression. Furthermore, initial response assessment by conventional imaging is often unable to identify which patients will achieve durable clinical benefit (DCB). Here, we demonstrate that pre-treatment circulating tumor DNA (ctDNA) and peripheral CD8 T cell levels are independently associated with DCB. We further show that ctDNA dynamics after a single infusion can aid in identification of patients who will achieve DCB. Integrating these determinants, we developed and validated an entirely noninvasive multiparameter assay (DIREct-On, Durable Immunotherapy Response Estimation by immune profiling and ctDNA-On-treatment) that robustly predicts which patients will achieve DCB with higher accuracy than any individual feature. Taken together, these results demonstrate that integrated ctDNA and circulating immune cell profiling can provide accurate, noninvasive, and early forecasting of ultimate outcomes for NSCLC patients receiving ICIs.

Racial Diversity and Reporting in United States Food and Drug Administration Registration Trials for Thoracic Malignancies from 2006 to 2020.

There is significant racial disparity in thoracic malignancies in terms of epidemiology and outcomes. We analyzed race reporting and racial diversity in the registration trials of drugs approved by the FDA for thoracic malignancies from 2006 to 2020. We found a significant under-representation of non-white participants in FDA drug registration trials in thoracic malignancies. Furthermore, though almost all trials report some race information, FDA guidelines are not universally followed. There is a disproportionate disease burden of lung cancer in under-represented race communities, and clinical trials should prioritize racial diversity and inclusion efforts.

Improved survival and disease control following pembrolizumab-induced immune-related adverse events in high PD-L1 expressing non-small cell lung cancer with brain metastases.

INTRODUCTION: Immune checkpoint inhibitors have become standard of care for many patients with non-small cell lung cancer (NSCLC). These agents often cause immune-related adverse events (IRAEs), which have been associated with increased overall survival (OS). Intracranial disease control and OS for patients experiencing IRAEs with metastatic NSCLC and brain metastases have not yet been described. METHODS: We performed a single-institution, retrospective review of patients with NSCLC and existing diagnosis of brain metastasis, who underwent pembrolizumab treatment and developed any grade IRAE. The primary outcome of the study was intracranial time to treatment failure (TTF), defined from time of pembrolizumab initiation to new intracranial disease progression or death. Kaplan-Meier and Cox proportional hazard analyses were performed. RESULTS: A total of 63 patients with NSCLC brain metastasis were identified, and 24 developed IRAEs. Patients with any grade IRAEs had longer OS (21 vs. 10 months, p = 0.004), systemic TTF (15 vs. 4 months, p < 0.001) and intracranial TTF (14 vs. 5 months, p = 0.001), relative to patients without IRAEs. Presence of IRAEs and high PD-L1 (≥ 50%), but not absent/moderate PD-L1 (0-49%), had a positive association for OS, systemic TTF, and intracranial TTF. Following multivariable analysis, IRAE experienced on pembrolizumab was an independent predictor of OS, systemic TTF, and intracranial TTF. CONCLUSIONS: In our series of patients with NSCLC and brain metastases treated with pembrolizumab, IRAE presence was associated with a significant increase in OS, systemic TTF, and intracranial TTF. Future studies with increased cohorts will clarify how IRAEs should be interpreted among molecular subtypes.

The Current State of Palliative Care for Patients Cared for at Leading US Cancer Centers: The 2015 NCCN Palliative Care Survey.

BACKGROUND: ASCO and IOM recommend palliative care (PC) across health care settings for patients with serious illnesses, including cancer. This study provides an overview of the current availability, structure, and basic quality of PC services within NCCN Member Institutions. METHODS: A PC survey was developed by NCCN staff and a working group of PC experts from 11 NCCN Member Institutions under the auspices of the NCCN Best Practices Committee. The survey was piloted and refined by 3 working group members and sent electronically to all 26 NCCN Member Institutions. NCCN staff and working group leaders analyzed the survey data. RESULTS: A total of 22 of 26 institutions responded (85%). All respondents (100%) reported an inpatient PC consult service (staffed by an average of 6.8 full-time equivalents [FTEs], seeing 1,031 consults/year with an average length of stay [LOS] of 10 days). A total of 91% of respondents had clinic-based PC (with an average of 469 consults/year, staffed by an average of 6.8 FTEs, and a 17-day wait time). For clinics, a comanagement care delivery model was more common than strict consultation. Home-based PC (23%) and inpatient PC units (32%) were less prevalent. Notably, 80% of institutions reported insufficient PC capacity compared with demand. Across PC settings, referrals for patients with solid tumors were more common than for hematologic malignancies. Automatic or "triggered" referrals were rare. The most common services provided were symptom management (100%) and advance care planning (96%). Most programs were funded through fee-for-service billing and institutional support. Partnerships with accountable care organizations and bundled payment arrangements were infrequent. PC program data collection and institutional funding for PC research were variable across institutions. CONCLUSIONS: Despite the prevalence of PC inpatient and clinic services among participating NCCN Member Institutions, PC demand still exceeds capacity. Opportunities exist for expansion of home-based PC and inpatient PC units, optimizing referrals, research, and payer collaborations.

A predictive model to identify hospitalized cancer patients at risk for 30-day mortality based on admission criteria via the electronic medical record.

BACKGROUND: This study sought to develop a predictive model for 30-day mortality in hospitalized cancer patients, by using admission information available through the electronic medical record. METHODS: Observational cohort study of 3062 patients admitted to the oncology service from August 1, 2008, to July 31, 2009. Matched numbers of patients were in the derivation and validation cohorts (1531 patients). Data were obtained on day 1 of admission and included demographic information, vital signs, and laboratory data. Survival data were obtained from the Social Security Death Index. RESULTS: The 30-day mortality rate of the derivation and validation samples were 9.5% and 9.7% respectively. Significant predictive variables in the multivariate analysis included age (P < .0001), assistance with activities of daily living (ADLs; P = .022), admission type (elective/emergency) (P = .059), oxygen use (P < .0001), and vital signs abnormalities including pulse oximetry (P = .0004), temperature (P = .017), and heart rate (P = .0002). A logistic regression model was developed to predict death within 30 days: Score = 18.2897 + 0.6013*(admit type) + 0.4518*(ADL) + 0.0325*(admit age) - 0.1458*(temperature) + 0.019*(heart rate) - 0.0983*(pulse oximetry) - 0.0123 (systolic blood pressure) + 0.8615*(O2 use). The largest sum of sensitivity (63%) and specificity (78%) was at -2.09 (area under the curve = -0.789). A total of 25.32% (100 of 395) of patients with a score above -2.09 died, whereas 4.31% (49 of 1136) of patients below -2.09 died. Sensitivity and positive predictive value in the derivation and validation samples compared favorably. CONCLUSIONS: Clinical factors available via the electronic medical record within 24 hours of hospital admission can be used to identify cancer patients at risk for 30-day mortality. These patients would benefit from discussion of preferences for care at the end of life.

Study of Patient and Physician Attitudes Toward Automated Prognostic Models for Patients With Metastatic Cancer.

PURPOSE: For patients with cancer and their doctors, prognosis is important for choosing treatments and supportive care. Oncologists' life expectancy estimates are often inaccurate, and many patients are not aware of their general prognosis. Machine learning (ML) survival models could be useful in the clinic, but there are potential concerns involving accuracy, provider training, and patient involvement. We conducted a qualitative study to learn about patient and oncologist views on potentially using a ML model for patient care. METHODS: Patients with metastatic cancer (n = 15) and their family members (n = 5), radiation oncologists (n = 5), and medical oncologists (n = 5) were recruited from a single academic health system. Participants were shown an anonymized report from a validated ML survival model for another patient, which included a predicted survival curve and a list of variables influencing predicted survival. Semistructured interviews were conducted using a script. RESULTS: Every physician and patient who completed their interview said that they would want the option for the model to be used in their practice or care. Physicians stated that they would use an AI prognosis model for patient triage and increasing patient understanding, but had concerns about accuracy and explainability. Patients generally said that they would trust model results completely if presented by their physician but wanted to know if the model was being used in their care. Some reacted negatively to being shown a median survival prediction. CONCLUSION: Patients and physicians were supportive of use of the model in the clinic, but had various concerns, which should be addressed as predictive models are increasingly deployed in practice.

Plasma exchange for severe immune-related adverse events from checkpoint inhibitors: an early window of opportunity?

Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of several advanced malignancies leading to durable remission in a subset of patients. Their rapidly expanding use has led to an increased frequency of immune-related adverse events (irAEs). The pathogenesis of irAEs is poorly understood but may involve aberrant activation of T cells leading to inflammatory cytokine release or production of pathogenic antibodies leading to organ damage. Severe irAEs can be extremely debilitating and, in some cases, life threatening. IrAEs may not always be corticosteroid responsive or may require excessively high, often toxic, corticosteroid doses. Therapeutic plasma exchange (PLEX) is a treatment modality that has shown promising results for the management of certain severe irAEs, including irAEs that are not mentioned in current treatment guidelines. PLEX may attenuate ongoing irAEs and prevent delayed irAEs by accelerating clearance of the ICI, or by acutely removing pathogenic antibodies, cytokines, and chemokines. Here, we summarize examples from the literature in which PLEX was successfully used for the treatment of irAEs. We posit that timing may be a critical factor and that earlier utilization of PLEX for life-threatening irAEs may result in more favorable outcomes. In individuals at high risk for irAEs, the availability of PLEX as a potential therapeutic mitigation strategy may encourage life-saving ICI use or rechallenge. Future research will be critical to better define which indications are most amenable to PLEX, particularly to establish the optimal place in the sequence of irAE therapies and to assess the ramifications of ICI removal on cancer outcomes.

EGFR exon 20 Insertion NSCLC and Response to Platinum-Based Chemotherapy.

INTRODUCTION: In classical EGFR mutant non-small-cell lung cancer (NSCLC), EGFR tyrosine kinase inhibitor (TKI) therapy yields better outcomes than platinum-based chemotherapy. However, EGFR exon 20 insertion (ex20ins) NSCLC is relatively resistant to currently available EGFR TKIs. Though platinum-based chemotherapy is the frontline standard of care for EGFR ex20ins NSCLC, its efficacy is not fully described. STUDY DESIGN: A retrospective, single-center, case series METHODS: Patients were identified through an electronic research database at a single institution and included if they had advanced EGFR ex20ins NSCLC, received platinum-based chemotherapy for metastatic disease, and had scans evaluable for response. Each patient's demographics, tumor characteristics, and clinical course were recorded. Treatment response was evaluated using RECIST v1.1 criteria, and the PFS was calculated by the Kaplan-Meier method. RESULTS: Among 27 patients identified with EGFR ex20ins NSCLC at our institution, 18 (67%) received platinum-based chemotherapy for metastatic disease and had scans evaluable for response. These patients received platinum-based chemotherapy in the first-line (N = 17, 94%) and second-line settings (N = 1, 6%). The objective response rate (ORR) to platinum-based chemotherapy was 39% (7 of 18 patients; 95% confidence interval [CI] 16-61). The median PFS with platinum-based chemotherapy was 7.1 months (95% CI, 6.3 -13.7), and the median overall survival was 3.2 years (95% CI, 1.92 - NR). CONCLUSIONS: The efficacy of platinum-based chemotherapy in EGFR ex20ins NSCLC is similar to that expected for TKI sensitive EGFR mutant NSCLC. Novel agents designed to specifically target ex20ins mutant EGFR should additionally improve outcomes.

Circulating Tumor DNA Dynamics Predict Benefit from Consolidation Immunotherapy in Locally Advanced Non-Small Cell Lung Cancer.

Circulating tumor DNA (ctDNA) molecular residual disease (MRD) following curative-intent treatment strongly predicts recurrence in multiple tumor types, but whether further treatment can improve outcomes in patients with MRD remains unclear. We applied CAPP-Seq ctDNA analysis to 218 samples from 65 patients receiving chemoradiation therapy (CRT) for locally advanced NSCLC, including 28 patients receiving consolidation immune checkpoint inhibition (CICI). Patients with undetectable ctDNA after CRT had excellent outcomes whether or not they received CICI. Among such patients, one died from CICI-related pneumonitis, highlighting the potential utility of only treating patients with MRD. In contrast, patients with MRD after CRT who received CICI had significantly better outcomes than patients who did not receive CICI. Furthermore, the ctDNA response pattern early during CICI identified patients responding to consolidation therapy. Our results suggest that CICI improves outcomes for NSCLC patients with MRD and that ctDNA analysis may facilitate personalization of consolidation therapy.

KEAP1/NFE2L2 Mutations Predict Lung Cancer Radiation Resistance That Can Be Targeted by Glutaminase Inhibition.

Tumor genotyping is not routinely performed in localized non-small cell lung cancer (NSCLC) due to lack of associations of mutations with outcome. Here, we analyze 232 consecutive patients with localized NSCLC and demonstrate that KEAP1 and NFE2L2 mutations are predictive of high rates of local recurrence (LR) after radiotherapy but not surgery. Half of LRs occurred in tumors with KEAP1/NFE2L2 mutations, indicating that they are major molecular drivers of clinical radioresistance. Next, we functionally evaluate KEAP1/NFE2L2 mutations in our radiotherapy cohort and demonstrate that only pathogenic mutations are associated with radioresistance. Furthermore, expression of NFE2L2 target genes does not predict LR, underscoring the utility of tumor genotyping. Finally, we show that glutaminase inhibition preferentially radiosensitizes KEAP1-mutant cells via depletion of glutathione and increased radiation-induced DNA damage. Our findings suggest that genotyping for KEAP1/NFE2L2 mutations could facilitate treatment personalization and provide a potential strategy for overcoming radioresistance conferred by these mutations. SIGNIFICANCE: This study shows that mutations in KEAP1 and NFE2L2 predict for LR after radiotherapy but not surgery in patients with NSCLC. Approximately half of all LRs are associated with these mutations and glutaminase inhibition may allow personalized radiosensitization of KEAP1/NFE2L2-mutant tumors.This article is highlighted in the In This Issue feature, p. 1775.

Palliative care clinicians and online education in India: a survey.

BACKGROUND: Whether online resources can facilitate spread of palliative care knowledge and skills in India is an urgent question given few providers and a large, ageing population. OBJECTIVES: We surveyed needs and feasibility regarding e-learning. METHODS: Indian, Australian and North American palliative care experts developed an electronic survey using Qualtrics, emailed to all registrants of the 2017 Indian Association of Palliative Care (IAPC) conference and distributed during the conference. RESULTS: Of 60 respondents (66% men, 60% doctors), most worked in hospitals and had oncology backgrounds, and 35% were from Kerala and Tamil Nadu. Most (90.9%) received palliative care training in India or overseas with 41% trained in a Trivandrum Institute of Palliative Sciences residential course (4-6 weeks). 17% completed the IAPC essential certificate and 22% had undertaken various distance learning courses. Interest in online training was substantial for most aspects of palliative care. CONCLUSION: There was a high level of interest and reported feasibility in taking a case-based online course. This pilot survey provides support for online case-based education in India, particularly among physicians.

Phase II trial of single agent amrubicin in patients with previously treated advanced thymic malignancies.

OBJECTIVES: There are limited treatment options for patients with thymic malignancies. Here we present data supporting treatment with single agent amrubicin, a third generation anthracycline and topoisomerase II inhibitor. MATERIALS AND METHODS: This was a phase 2 open-label, single arm trial of amrubicin in patients with thymoma (T) or thymic carcinoma (TC), conducted at two academic institutions. Patients were included if they had received at least one prior chemotherapy regimen. The first 18 patients received amrubicin at 40 mg/m2 IV days 1-3 repeated every 3-weeks. Due to the high incidence of febrile neutropenia, dosing was subsequently amended to 35 mg/m2 for the final 15 patients. RESULTS: A total of 33 patients (14 T/19 TC) were enrolled from 2011 to 2014. Median number of prior therapies was 2. Best response included 6 partial responses, 21 stable disease, and 6 progressive disease (all TC). Objective response rate was 18% (90% exact binomial CI 8.2%-32.8%; T = 4/14 (29%), TC = 2/19 (11%)). Median progression-free survival was 7.7 months (T: 8.3 months; TC: 7.3) and median overall survival was 29.7 months (T: 54.1 months; TC: 18 months). There was a high rate of febrile neutropenia (7 patients) that occurred despite a reduction in amrubicin dose and one related death. Five patients had reduction in LVEF below 50% during the course of treatment resulting in treatment discontinuation in one patient. CONCLUSION: Amrubicin shows promise as a single agent in heavily pre-treated patients with thymic malignancies. Notable side effects include febrile neutropenia and the use of growth factor support is essential. Further investigation of this agent is warranted.